Highly active antiretroviral therapy (HAART) has led to profound and prolonged reductions in circulating virus in many HIV-infected individuals. Nevertheless, the AIDS pandemic continues to spread unchecked in many parts of the world. The use of HAART is limited by high cost, side effects, poor compliance to complex drug regimens and by the emergence of multi-drug resistant virus strains. Fortunately, a new class of antiviral agents that target discrete steps in the virus entry pathway has recently emerged. At least a dozen different entry inhibitors are in clinical trials, with one (T-20) having been licensed by the FDA in 2003. As with other antiretrovirals, T-20 also selects for resistant HIV-1 strains in some cases, especially if it is not used in the most efficaciously. This fellowship application proposes studies aimed at identifying viral determinants that influence sensitivity to T-20 (Aim 1), and characterizing mechanisms of T-20 resistance in HIV-infected patients (Aim 2). Identification of viral determinants of T-20 sensitivity might have prognostic value and help direct more efficacious treatment in the clinic. Identifying resistance mechanisms will not only to help guide therapy, but also determine how resistance affects virus fitness and sensitivity to other entry inhibitors. Characterizing resistance mechanisms will also provide information about the complex conformational changes undergone by Env that mediate membrane fusion and virus entry. [unreadable] [unreadable]